We are using inbred mouse strains that develop high spontaneous incidences of retrovirally induced leukemia as model systems for identifying new leukemia disease genes. The expectation is that some of these genes will also represent human disease genes that might not be easy to identify directly in humans. Once these genes are identified, we use gene knockout and transgenic mice, genetic criteria, and cell biological approaches to understand how these genes function in disease induction, to place these genes into different biochemical pathways, and to develop new mouse models for human leukemia. The BXH2 and AKXD recombinant inbred strains have been particularly valuable for this research because they develop high incidences of myeloid or B- and T-cell leukemia, respectively, and the proviral integration sites in these leukemias provide powerful genetic tags for disease gene identification. Insertional mutagenesis studies performed in ours and other laboratories have identified more than 250 candidate cancer gene loci. Several of these loci encode validated human cancer genes, while many others encode novel genes that have not yet been examined for a role in human or mouse disease. These are the most interesting since they represent potential novel new human cancer genes. Many of these genes function in pathways already associated with hematopoietic disease, while others may identify pathways not yet associated with hematopoietic disease. In many tumors more than one disease gene was identified by insertional mutagenesis. These genes are likely to represent cooperating partners in disease. Finally, several genes identified by insertional mutagenesis have been shown to function as key regulators of normal hematopoiesis. Insertional mutagenesis therefore also provides a way to identify new regulators of hematopoiesis.